slide 1 the medical therapy of prostatic symptoms (mtops) trial: results
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Slide 2
Medical Treatment of BPH: The Challenge
BPH is the most common benign neoplasm in older men
Clinical BPH involves benign prostatic enlargement, lower urinary tract symptoms (LUTS), and bladder outlet obstruction
BPH can interfere with daily activities and can diminish health-related quality of life specificto urinary symptoms
BPH=benign prostatic hyperplasia
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243; Emberton M et al Urology 2003;61(2):267-273; Girman CJ et al Eur Urol 1999;35:277-284.
Slide 3
Medical Treatment of Clinical BPH
Adapted from Chatelain C et al 5th International Consultation on BPH 2001:519-535.
Recommendations of the 5th International Consultation on BPH in 2001
Prevent complications
Minimize adverse effects of treatment
Preserve quality of life
Improve symptomsShort-term
Long-term
Overall
Slide 4
Medical Treatment of Clinical BPH
5-alpha reductase inhibitors and alpha blockers are the only recommended medical treatments of BPH
Recommendations for phytotherapy or polyene derivatives require additional long-term data
Adapted from Chatelain C et al 5th International Consultation on BPH 2001:519-535.
Recommendations of the 5th International Consultation on BPH in 2001
Slide 5
Could Combination Therapy Be a Better Approach?
Two-Drug Therapy Activates Two Distinct and Complementary Mechanisms of Action
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.
Alpha blockers 5-Alpha reductase inhibitors
Improve symptoms and increase urinary flow rate by relaxing prostatic and bladder-neck smooth muscle through sympathetic activity blockade
Improve symptoms, increase urinary flow rate, and prevent BPH outcomes by reducing prostate enlargement through hormonal mechanisms
Slide 6
Evidence on Combination Therapy
Most trials of 5-alpha reductase inhibitor + alpha-blocker therapy were of short duration or lacked placebo controls
Two randomized, placebo-controlled, multicenter, 12-month studies showed that combination therapy did not enhance the efficacy of alpha-blocker monotherapy in terms of improving symptoms or urinary flow rate– VA COOP: Placebo vs. PROSCAR™ vs. terazosin vs.
combination in 1229 men with BPH in US VA system
– PREDICT: Placebo vs. PROSCAR vs. doxazosin vs. combination in 1095 men with BPH in Europe
PROSCAR (finasteride) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
VA COOP=Veterans Affairs Cooperative; PREDICT=Prospective European Doxazosin and Combination Therapy
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; Debruyne FMJ et al Eur Urol 1998;34:169-175; Savage SJ et al Can J Urol 1998;5(3):578-584; Lepor H et al N Engl J Med 1996;335(8):533-539; Kirby RS et al Urology 2003;61(1):119-126.
Slide 7
Objective of MTOPS
Independently Conducted by the US National Institutes of Health (NIH)
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
MTOPS (Medical Therapy Of Prostatic Symptoms)
To determine whether long-term medical therapy with PROSCAR™, the alpha blocker doxazosin,
or their combination would prevent or delay the clinical progression of BPH
Slide 8
Study Design: Overview
Double-blind, placebo-controlled, multicenter, randomized Average follow-up: 4.5 years
AUA=American Urological Association; Qmax=maximum urinary flow
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
RandomizedN=3047
Entry Criteria
• Men 50 years of age• AUA symptom score 8–
30• Qmax 4–15 ml/sec• Voided volume 125 ml
Doxazosin(n=756)
PROSCAR™
(n=768)
PROSCAR +doxazosin
(n=786)
Placebo(n=737)
MTOPS (Medical Therapy Of Prostatic Symptoms)
Slide 9
Clinical progression of BPH– Confirmed 4-point increase in AUA-SI– AUR– Recurrent urinary tract infections/
urosepsis– Urinary incontinence– Renal insufficiency
Natural history of BPH with respect to– BPH symptoms– Qmax
– Prostate volume– Sexual function– Quality of life
Study Design: Outcomes
Primary outcome
AUA-SI=American Urological Association Symptom Index; AUR=acute urinary retention
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
Secondaryoutcome
MTOPS (Medical Therapy Of Prostatic Symptoms)
Slide 10
Characteristic Value*
Age (years) 62.0
AUA-SI score 17.0
TRUS Prostate volume (cc) 31.0
Postvoid residual urine volume (ml) 39.0
Qmax (ml/second) 10.6
AUA=American Urological Association; TRUS=transrectal ultrasound
*Values are medians
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
No significant differences between groups
Baseline Characteristics of Patients MTOPS (Medical Therapy Of Prostatic Symptoms)
Slide 11
Impact of Medical Therapy on Clinical Progression of BPH
P values are for the comparison with placebo.
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Cumulative incidence of BPH progression
66%risk
reduction(p<0.001)
25
20
15
10
5
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Per
cen
tag
e w
ith
eve
nt
Years from randomization
Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)
MTOPS (Medical Therapy Of Prostatic Symptoms)
p=0.002
p<0.001
p<0.001
Slide 12
Most BPH Progression Events Were Due to Symptom Progression
Distribution of BPH progression events
MTOPS (Medical Therapy Of Prostatic Symptoms)
UTI=urinary tract infection
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
>4-point AUA-SIincrease 80%
AUR12%
Incontinence 7%UTI/urosepsis 1%Renal insufficiency 0%
Slide 13
Impact of Medical Therapy on Symptom Control
*AUA-SI score
Adapted from McConnell JD. Presentation at AUA Annual Meeting, Orlando, Florida, USA, May 2002; Bautista OM et al Control Clin Trials 2003;24:224-243.
MTOPS (Medical Therapy Of Prostatic Symptoms)
Cumulative incidence of 4-point increase in symptom score*
25
20
15
10
5
0
Per
cen
tag
e w
ith
eve
nt
Years from randomization
Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
64%risk
reduction(p<0.0001)
Slide 14
Effect of Medical Therapy on Prostate Volume
*p<0.001 vs. baseline
Adapted from McConnell JD. Presentation at AUA Annual Meeting, Orlando, Florida, USA, May 2002; Bautista OM et al Control Clin Trials 2003;24:224-243.
MTOPS (Medical Therapy Of Prostatic Symptoms)
Change from baseline in prostate volume
–20 –10 0 10 20
Median % change from baseline
–16%*
–13%*
+18%
+18%
Combination (PROSCAR™ + doxazosin) (n=786)
PROSCAR (n=768)
Placebo (n=737)
Doxazosin (n=756)
Slide 15
81%risk
reduction(p<0.001)
Impact of Medical Therapy on the Risk of AUR
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Cumulative incidence of AUR
3.5
3.0
2.5
2.0
1.5
1.0
0.5
00 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Per
cen
tag
e w
ith
eve
nt
Years from randomization
MTOPS (Medical Therapy Of Prostatic Symptoms)
Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)
p<0.001
p=0.009
Slide 16
Impact of Medical Therapy on the Need for Invasive BPH Therapy*
*Endoscopic (e.g., transurethral prostatectomy) or open surgeries primarily; other therapies were minimally invasive (e.g., transurethral microwave therapy)Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Cumulative incidence of BPH-related surgery
10
8
6
4
2
0
Per
cen
tag
e w
ith
eve
nt
Years from randomization
Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)
MTOPS (Medical Therapy Of Prostatic Symptoms)
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
67%risk
reduction(p<0.001)
p<0.001
p<0.001
Slide 17
PROSCAR Placebo Doxazosin PROSCAR™ and doxazosin
Variable (n=737) (n=756) (n=768) (n=786)
*The numbers shown are the rates per 100 person-years of follow-up (incidence density) as of September 30, 2002; **p<0.05 vs. placebo
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Medical Monotherapy and Combination Therapy Demonstrated Long-Term Tolerability
MTOPS (Medical Therapy Of Prostatic Symptoms)
Ten most frequent adverse events among groups*
Adverse EventErectile dysfunction 3.3 3.6 4.5** 5.1**Dizziness 2.3 4.4** 2.3 5.4**Postural hypotension 2.3 4.0** 2.6 4.3**Asthenia 2.1 4.1** 1.6 4.2**Decreased libido 1.4 1.6 2.4** 2.5**Abnormal ejaculation 0.8 1.1 1.8** 3.1**Peripheral edema 0.7 0.9 0.7 1.3**Dyspnea 0.6 0.9 0.6 1.2**Allergic reaction 0.5 0.9** 0.6 0.7Somnolence 0.4 0.8** 0.4 0.8**
Total no. of person-years 3489 3652 3600 3832
Slide 18
Conclusions
Combination therapy is the most effective form of medical therapy for BPH
– 66% reduction in risk of BPH progression (p<0.001*)
– 64% reduction in worsening symptoms (p<0.001*)
– 81% reduction in risk of AUR (p<0.001*)
– 67% reduction in need for invasive BPH therapy (p<0.001*)
Long-term monotherapy and combination therapy were well tolerated and effective
MTOPS (Medical Therapy Of Prostatic Symptoms)
*vs. placebo at 4 years
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
Slide 19
The Future of Combination Therapy for BPH
Adapted from NIH news release. Available at: http://www.nih.gov/news/pr/may2002/niddk-28.htm.
Leroy M. Nyberg Jr, PhD, MD Director, Urology ProgramNational Institute of Diabetes and Digestive and Kidney Diseases
“The evidence supporting combination therapy [for BPH]
in selected patients is so strong that I expect to see
major changes in medical practice in the near future.”
Slide 21
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved. 3-05 PSC 2004-W-14295-SS Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
MTOPS: Medical Therapy Of Prostatic Symptoms
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in this slide presentation, please consult the manufacturers’
prescribing information.